Early Stages Of Disease Research Articles

G-Protein-Coupled Receptor-Associated Sorting Protein 1 Overexpression Is Involved in the Progression of Benign Prostatic Hyperplasia, Early-Stage Prostatic Malignant Diseases, and Prostate Cancer.

Background/Objectives: Prostate cancer (PCa) is a prevalent malignancy, necessitating accurate diagnostic methods to distinguish it from benign conditions such as benign prostatic hyperplasia (BPH). Current diagnostic tools, relying primarily on serum prostate-specific antigen (PSA) levels, lack specificity, leading to an over-diagnosis and unnecessary treatment of patients with benign conditions. This study explores G-protein-coupled receptor-associated sorting protein 1 (GASP-1) as a more sensitive biomarker for PCa detection. Methods: Prostate tissue microarrays of healthy, BPH, and prostate cancer patients with different Gleason scores were studied. Polyclonal antibodies targeted against GASP-1 were used for routine immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA) analyses. Results: The results indicated a 5-fold difference in serum GASP-1 levels between BPH and PCa, which was validated through GASP-1 IHC. Furthermore, a novel scoring system, the H-score, assesses GASP-1 granules' intensity and size, revealing a clear distinction between BPH and PCa. An additional analysis of GASP-1 expression between PCa cases with different Gleason scores reveals that GASP-1 overexpression correlates with PCa severity, providing insights into disease progression. Conclusions: The study supports GASP-1's role as a promising diagnostic marker, supplementing PSA testing, and offering improved risk stratification for PCa. Additionally, an open-source software system is introduced for an efficient GASP-1 granule color analysis, enhancing diagnostic accuracy.

Automatic Method of Macular Diseases Detection Using Deep CNN-GRU Network in OCT Images

Abstract The increasing development of Deep Learning mechanism allowed ones to create semi-fully or fully automated diagnosis software solutions for medical imaging diagnosis. The convolutional neural networks are widely applied for central retinal diseases classification based on OCT images. The main aim of this study is to propose a new network, Deep CNN-GRU for classification of early-stage and end-stages macular diseases as age-related macular degeneration and diabetic macular edema (DME). Three types of disorders have been taken into consideration: drusen, choroidal neovascularization (CNV), DME, alongside with normal cases. The created automatic tool was verified on the well-known Labelled Optical Coherence Tomography (OCT) dataset. For the classifier evaluation the following measures were calculated: accuracy, precision, recall, and F1 score. Based on these values, it can be stated that the use of a GRU layer directly connected to a convolutional network plays a pivotal role in improving previously achieved results. Additionally, the proposed tool was compared with the state-of-the-art of deep learning studies performed on the Labelled OCT dataset. The Deep CNN-GRU network achieved high performance, reaching up to 98.90% accuracy. The obtained results of classification performance place the tool as one of the top solutions for diagnosing retinal diseases, both early and late stage.

Lung cancer screening: Real screening site data, Vojvodina, Serbia

Abstract Background Lung cancer (LC) is the top cause of cancer-related deaths globally and in Serbia, often diagnosed in advanced stage of disease with when 5-year survival is 10% to 20%. LC screening with low-dose CT (LDCT) can decrease LC mortality and overall mortality. The first pilot LC screening program in Serbia started in the Institute for Pulmonary Diseases of Vojvodina in September 2020. The main objective of this study was to analyze LC patient characteristics according to their screening status. Methods This retrospective study utilized LC hospital registry data from September 2020 to December 2023, including gender, age at diagnosis, settlement area, smoking habits, cancer histological type, TNM classification, disease stage (1-4), and data on participation in LC screening. Group differences were assessed using chi-square and Student’s t-tests, with analyses conducted in SPSS v24.0. Results During observed period from a total of 4649 LC cases 2948 (63.4%) were males, and 73 (1.6%) were included in LC screening. Average age of all LC patients was 66 years, without differences between groups (p = 0.778). Significant differences between groups by gender were find (p = 0.042). Non-screened LC patients were significantly common males compared to females (63.6% vs 36.4%), while among screened difference by gender were lower (52.1% vs 47.9%, respectively). Screened compared to non-screened LC patients have significantly lower percentage of SCLC (9.6% vs 19.1%), and higher percentage of NSCLC (90.4% vs 80.9%), (p = 0.040). According to LC stage, screened compared to non-screened patients were significantly common diagnosed in stage I of disease (45.8% vs 7.8%), and significantly less common in higher LC stages; stage IIIB (11.1% vs 22.5%), and in stage IV (22.2% vs 45.7%), (p < 0.001). Conclusions LC screening with LDCT is proven secondary preventive measure with significant influence on decreasing LC mortality by increasing number of LC patients in early stages of disease. Key messages • Lung cancer screening with low-dose CT significantly increases early-stage diagnoses, improving survival chances. • Population strategies to prevent smoking and screening programs for high-risk groups are needed to reduce lung cancer incidence and mortality rates in Serbia.

Effect of trimetazidine dihydrochloride therapy on myocardial external efficiency in preclinical individuals with an HCM sarcomeric gene mutation

Abstract Background Hypertrophic cardiomyopathy (HCM) is frequently caused by pathogenic gene variants, i.e. mutations in genes encoding sarcomere proteins. Previous studies have shown that preclinical asymptomatic individuals with a heterozygous sarcomere mutation have decreased myocardial external efficiency (MEE), which is thought to be a key pathomechanism in the onset and progression of HCM. Purpose In the ENERGY trial, preclinical individuals with an HCM sarcomere gene mutation without hypertrophy were treated with the metabolic anti-anginal drug trimetazidine (TMZ) to determine whether the reduced MEE can be corrected at an early pre-hypertrophic disease stage. Methods 40 MYBPC3 and MYH7 asymptomatic mutation carriers without hypertrophy were treated for eight weeks with TMZ or placebo in a double-blind randomized study design. Directly before and after treatment, study participants underwent an [11C]-acetate PET/CT-scan and cardiac magnetic resonance imaging to measure MEE. A cardio-pulmonary exercise test was performed to measure the influence of TMZ on exercise parameters. Results Eight weeks of treatment with TMZ 20mg three times daily did not significantly alter MEE compared to placebo. The mean MEE changed from 30.3±3.8 percent to 29.8±4.3 percent in the placebo group and from 30.1±4 percent to 29.1±4 percent in the TMZ group. After adjustment for baseline, the TMZ group did not have a significantly different MEE (95% CI, -2.863 to 1.986, P=0.68) compared to placebo. Exercise parameters VO2max and respiratory exchange ratio were not significantly altered by treatment with TMZ. Conclusion The ENERGY trial is the first proof-of-concept randomized controlled trial with well-matched (age, sex, mutation) groups to test the hypothesis that TMZ improves MEE at a preclinical disease stage. We conclude that metabolic therapy does not correct reduced MEE in an early disease stage of HCM.methodsprimary outcome

New clinical staging proposal applied to a Fabry cardiomyopathy cohort

Abstract Background Fabry disease (FD) is a rare cause of hypertrophic cardiomyopathy (HCM), and early diagnosis is important considering the response to enzyme replacement or chaperone therapies. Recently, a practical clinical staging for Fabry cardiomyopathy was proposed by Olivotto et al 2023, considering several features, being potentially useful for standardizing the criteria for initiation and response assessment to therapy. Imaging characterization of hypertrophy and fibrosis are critical key items to determine stages. This new proposal suggested 4 main stages (0, I, II, III) according to these parameters. Stages 0 and I are further divided in 2 sub-stages according to minor findings and hypertrophy severity, respectively. Unfortunately, not all patients with Fabry cardiomyopathy are identified early in the disease, limiting the response to treatment. Aim Our study aimed to evaluate retrospectively the staging of Fabry cardiomyopathy at first imaging cardiac evaluation according to the recent proposal (1), in a cohort of 35 patients with FD at a reference centre of Fabry disease. Results At the first cardiac evaluation, the group of patients had a median age of 46 years (28-68 years), 69% were female and 5% were already under enzymatic therapy. The majority of Fabry patients (66%) were in non-hypertrophic stage 0: 4 patients in 0A with no detected cardiac involvement and 19 patients in 0B with subclinical cardiac findings (17% presenting diastolic dysfunction, 14% impaired global longitudinal strain, 6% hypertrabeculation, 6% reduced native T1, 3% short PR duration, 3% cardiac symptoms). In hypertrophic stage I, 14% of patients were classified according to the presence and severity of LVH: 3 in IA (12-15 mm) and 2 in IB (>15mm). All patients (n=3, 9%) in hypertrophic fibrotic stage II presented non-extensive late enhancement (< 3 LV segments) in the first CMR. Patients with overt dysfunction or stage III (n=4; 11%), presented diffuse myocardial fibrosis (> 3 LV segments) or impaired systolic function (LVEF < 50%). Conclusion In our cohort patients, the new staging scheme allows us to identify and classify the different stages of FD cardiomyopathy. The majority of patients were unexpectedly identified in early disease stages, but that could be related to diagnosis in the context of familial screening. This proposal seems useful for clinical staging standardization to facilitate the evaluation of responses to treatments and to predict outcomes, however, needs to be validated in larger and prospective studies.

The role of semi-quantitative parameters of thallium-201 myocardial perfusion imaging in predicting mortality rate among CKD population

Abstract Background Chronic kidney disease (CKD) is a major public health concern worldwide, with high morbidity and mortality rates. Myocardial perfusion imaging (MPI) is a non-invasive diagnostic tool that can detect early-stage cardiovascular disease in CKD patients. Purpose This study aimed to investigate the role of semi-quantitative parameters of Thallium-201 MPI in predicting mortality rates among CKD patients. Methods This retrospective study included 579 CKD patients who underwent Thallium-201 MPI between October 2005 and December 2019. Semi-quantitative parameters were analyzed using automation software, including transient ischemic dilation (TID), lung-to-heart ratio (LHR), total perfusion deficit (TPD), summed stress score (SSS), summed rest score (SRS), summed difference score (SDS), summed thickening percent (ST%), summed motion percent (SM%), stress end-diastolic volume (EDV), stress end-systolic volume (ESV), and stress left ventricular ejection fraction (LVEF). The primary endpoint was overall mortality. Results During a median follow-up of 52 months, 148 patients died. The older age group, lower hemoglobin levels, and lower estimated glomerular filtration rate (eGFR) were associated with higher mortality rates. The semi-quantitative parameters that predicted overall mortality included LHR above 0.4, elevated ST% , increased stress EDV and ESV, and reduced stress LVEF in a multivariable Cox regression model. Conclusion Thallium-201 MPI with semi-quantitative parameters can predict mortality rates in CKD patients without a definite diagnosis of coronary artery disease. The identified parameters, including LHR above 0.4, elevated ST levels, increased stress EDV and ESV, and reduced stress LVEF can assist in early detection the mortality risk in CKD patients.Characteristics of CKD PatientsMultivariable Analysis

Closing the Gaps: Testing the Efficacy of Carbapenem and Cephalosporin Treatments of Late-Stage Anthrax in Rabbits

Anthrax is a fatal zoonotic disease caused by exposure to Bacillus anthracis spores. The CDC’s guidelines divide anthrax treatment into three categories according to disease progression: post-exposure prophylaxis (PEP), systemic, and systemic with a suspicion of CNS infection. While the prognosis for PEP or the early treatment of systemic anthrax is very good, ingress of the bacteria into the CNS poses a substantial clinical challenge. Here, we use rabbits to test the efficacy of a combined treatment of meropenem and doxycycline, which is the first choice in the CDC recommendations for treating systemic patients with an indication of CNS infection. In addition, we test the efficacy of the first-generation cephalosporin, cefazolin, in treating different stages of the disease. We found that the combination of doxycycline and meropenem is highly effective in treating rabbits in our inhalation model. Cefazolin was efficient only for PEP or systemic-stage treatment and not for CNS-infected animals. Our findings support the CDC recommendation of using a combination of doxycycline and meropenem for systemic patients with or without indications of CNS infection. We found that cefazolin is a decent choice for PEP or early-stage systemic disease but recommend considering using this antibiotic only if all other options are not available.

Burst-like transcription of MYH7, allelic and contractile imbalance already in early stage hiPSC-cardiomyocytes indicate these as pathogenic factors in Hypertrophic Cardiomyopathy

Abstract Background Hypertrophic Cardiomyopathy (HCM) is caused by heterozygous mutations in sarcomeric proteins, which can cause hyper- or hypocontractiliy of cardiomyocytes. Previously we also observed highly variable force generation (contractile imbalance) among individual cardiomyocytes of HCM-patients with myosin (MYH7) or myosin-binding-protein-C mutations (MYBPC3), ranging from normal to highly altered values. Contractile imbalance is presumably caused by stochastic, burst-like transcription of mutant and wildtype allele, which induces unequal ratios of mutant vs. wildtype mRNA among individual cardiomyocytes. Variable force generation most likely is the result of also unequal fractions of mutated protein from cell to cell. Aim With this study we aimed to examine whether in addition to the effects of the mutation on sarcomere function, also allelic and contractile imbalance already exist at the beginning of disease development or whether both result from disease-related alterations in symptomatic HCM-patients. Methods and Results We studied this in patient-derived human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) with MYH7-mutation R723G as model for an early disease stage. These early, fetal-like cardiomyocytes developed typical HCM-related features like hypertrophy and increased myofibrillar disarray compared to WT-hiPSC-CMs. Calcium sensitivity was reduced, twitch kinetics were slowed down. To test whether MYH7 in these early-stage hiPSC-CMs also is transcribed in bursts or continuously, we performed RNA-fluorescence in situ hybridization (RNA-FISH). Nuclei without, with one and with two or more active transcription sites were observed which indicates stochastic, burst-like and independent transcription of the two MYH7-alleles. Ratios of mRNA from both alleles were quantified in individual cardiomyocytes by allele-specific single cell RT-PCR. We found highly variable ratios of mutated vs. wildtype mRNA among individual cardiomyocytes, similar to HCM-patient’s cardiac tissue, indicating unequal expression of mutant and wildtype mRNA from cell-to-cell. Furthermore, functional measurements on myofibrils from R723G-hiPSC-CMs revealed substantial variability in force generation at physiological calcium, compared to much smaller heterogeneity among WT-hiPSC-CMs. In addition, variability of twitch kinetics of intact hiPSC-CMs was also substantially increased among R723G- compared to WT-hiPSC-CMs. Altogether, this suggests that functional heterogeneity results from burst-like transcription in heterozygous HCM cardiomyocytes. Conclusions Our results in HCM-patient derived hiPSC-cardiomyocytes with a fetal-like developmental stage suggest that allelic and contractile imbalance among individual cardiomyocytes together with the mutation are present at the beginning of the disease. Thus, they most likely are exacerbating factors that contribute development of HCM hallmarks.

Exploring the complexity, treatment challenges, and outcomes in pediatric nodular lymphocyte predominant Hodgkin lymphoma: a perspective from a low-middle-income country.

In children, nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon subtype of Hodgkin lymphoma. Given the lack of data on the best chemotherapy regimen, there is a knowledge gap in best management. This retrospective study included all pediatric patients with NLPHL diagnosed and treated at the Children's Cancer Hospital, Egypt (2007-2018). We analyzed the clinical characteristics, and treatment outcome according to disease stage (early and advanced), treatment strategy (doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD] or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] and explored the prognostic factors for progression-free survival. The median age at diagnosis was 12 years; 40 (68%) patients had early-stage disease, and 19 (32%) had advanced-stage disease. The median follow-up was 70 months; the 5-year EFS and OS were 75% and 97%, respectively. The 5-year EFS was 78% for early-stage disease and 60% for advanced-stage disease; the 5-year OS was 100% for early-stage disease and 88% for advanced-stage disease. The patients who underwent R-CHOP had a better 3-year EFS (100%) compared with those who underwent ABVD (65%) regimen (P = 0.01). Seventeen (25%) patients relapsed: 9/40 (22%) had early-stage disease, and 8/19 (42%) had advanced-stage disease. Splenic involvement, mediastinal disease, extranodal disease, and slow early response were independent predictors of relapse risk. Pediatric patients with early-stage NLPHL have an excellent prognosis, with a 5-year OS of 100%. However, those with advanced stages had a high relapse rate. R-CHOP was associated with a better response and relapse-free rate than ABVD.

Immune system benefits of pulmonary rehabilitation in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a respiratory disease characterized by pulmonary and systemic inflammation. Inflammatory mediators show relationships with shortness of breath, exercise intolerance and health related quality of life. Pulmonary rehabilitation (PR), a comprehensive education and exercise training programme, is the most effective therapy for COPD and is associated with reduced exacerbation and hospitalization rates and increased survival. Exercise training, the primary physiological intervention within PR, is known to exert a beneficial anti-inflammatory effect in health and chronic diseases. The question of this review article is whether exercise training can also make such a beneficial anti-inflammatory effect in COPD. Experimental studies using smoke exposure mice models suggest that the response of the immune system to exercise training is favourably anti-inflammatory. However, the evidence about the response of most known inflammatory mediators (C-reactive protein, tumour necrosis factor α, interleukin 6, interleukin 10) to exercise training in COPD patients is inconsistent, making it difficult to conclude whether regular exercise training has an anti-inflammatory effect in COPD. It is also unclear whether COPD patients with more persistent inflammation are a subgroup that would benefit more from hypothesized immunomodulatory effects of exercise training (i.e., personalized treatment). Nevertheless, it seems that PR combined with maintenance exercise training (i.e., lifestyle change) might be more beneficial in controlling inflammation and slowing disease progress in COPD patients, specifically in those with early stages of disease.

A Narrative Review of the Clinical, Humanistic, and Economic Value of Pembrolizumab-Based Immunotherapy for the Treatment of Breast and Gynecologic Cancers.

Breast and gynecologic cancers are common across the world and are associated with substantial societal and economic burden. Pembrolizumab was among the first immune checkpoint inhibitors targeting programmed cell death protein1 to be approved for the treatment of patients with triple-negative breast cancer, cervical cancer, and endometrial cancer. Recent clinical trials have established pembrolizumab regimens as a standard of care treatment for these tumor types. Clinical data are further supported by patient-reported outcome, cost-effectiveness, and real-world evidence. Pembrolizumab monotherapy and combination regimens do not negatively influence health-related quality of life and are cost-effective relative to comparators. Ongoing phase3 studies with pembrolizumab will expand the current understanding of its use in breast and gynecologic cancers. Several of these studies are in patients with early-stage disease with the hope of curing patients. The main objective of this review is to summarize the clinical, humanistic, and economic value of pembrolizumab in these settings and to describe the future challenges for patients, caregivers, clinicians, and payers.

Oldie but Goldie: The Fundamental Role of Radioiodine in the Management of Thyroid Cancer.

Background/Objectives: The management of differentiated thyroid cancer (DTC) patients has undergone a major paradigm shift in past years, especially regarding the role of a careful postoperative disease assessment both in deciding for or against the use of iodine-131 therapy (i.e., patients' selection) and in selecting the correct goal of the treatment: ablative, adjuvant or therapeutic. Furthermore, diagnostic and risk-oriented uses of iodine isotopes (i.e., 123/124/131I) should always be considered during both postoperative assessment and follow-up of DTC patients to improve early staging and response assessment to initial treatments, respectively. The present review summarizes current (and real-life-related) evidence and the emerging perspectives on the therapeutic, diagnostic, and theragnostic use of radioiodine isotopes. Methods: A review of the pertinent literature was performed in PubMed, Web of Science, and Scopus without language restrictions or time limits and using one or more fitting search criteria and terms. Results: According to the literature evidence and real-life clinical practice, a risk-oriented postoperative iodine-131 therapy remains pivotal for most DTC patients and improves early disease staging through post-therapy functional imaging (i.e., theragnostic aim). Accordingly, the goal of iodine-131 therapy, the optimal strategy (empiric vs. dosimetric approach), the appropriate stimulation method [i.e., levothyroxine (L-T4) withdrawal vs. recombinant human thyrotropin (rhTSH) administration] and, finally, the suggested radioiodine activity to deliver for iodine-131 therapy (RIT) should be personalized, especially in metastatic DTC patients. Conclusions: The evidence related to the diagnostic and theragnostic use of iodine isotopes leads to a significant improvement in the postoperative risk stratification and staging of DTC patients in addition to a more accurate assessment of the response to initial treatments. In conclusion, radioiodine is really an oldie but goldie radiotracer. It has both a current fundamental role and a future perspective for the more careful management of DTC patients.

Raman spectroscopy reveals oxidative stress-induced metabolic vulnerabilities in early-stage AR-negative prostate-cancer versus normal-prostate cell lines

Quantitative Raman spectroscopy provides information-rich imaging of complex tissues. To illustrate its ability to characterise early-stage disease, we compared live P4E6, a low-grade Gleason-3 prostate-cancer cell line, to PNT2-C2, a normal prostate cell-line equivalent, thereby elucidating key molecular and mechanistic differences. Spectral changes from statistically relevant population sampling show P4E6 is defined by reduced DNA/RNA signatures (primarily base-pair modifications), increased protein-related signatures (synthesis), decreased whole-cell measured saturated and unsaturated fatty acids, and increased cholesterol and cholesterol ester (lipid storage). Signatures in the live-cell disease state point to the Warburg effect for aerobic glycolysis as the mechanism for cellular energy generation. A follow-on study involving catastrophic desiccation showed a key survival pathway in the cancer state in the structural robustness of DNA/RNA. Metabolic changes, namely in Warburg-to-oxidative-phosphorylation rerouting and reduced protein synthesis, were also shown. Such modifications limit cancer’s resistance to oxidative damage, and thus its ability to utilise a higher redox homeostasis for metabolic advantage. The results demonstrate the ability of quantitative Raman spectroscopy to uncover, with full molecular-heterogeneity capture, mechanistic vulnerabilities in lowest-grade tumorigenic prostate cancer, thereby revealing underlying targets for disease disruption at early stage.

Delineating three distinct spatiotemporal patterns of brain atrophy in Parkinson's disease.

The clinical manifestation of Parkinson's disease exhibits significant heterogeneity in the prevalence of non-motor symptoms and the rate of progression of motor symptoms, suggesting that Parkinson's disease can be classified into distinct subtypes. In this study, we aimed to explore this heterogeneity by identifying a set of subtypes with distinct patterns of spatiotemporal trajectories of neurodegeneration. We applied Subtype and Stage Inference (SuStaIn), an unsupervised machine learning algorithm that combined disease progression modelling with clustering methods, to cortical and subcortical neurodegeneration visible on 3 T structural MRI of a large cross-sectional sample of 504 patients and 279 healthy controls. Serial longitudinal data were available for a subset of 178 patients at the 2-year follow-up and for 140 patients at the 4-year follow-up. In a subset of 210 patients, concomitant Alzheimer's disease pathology was assessed by evaluating amyloid-β concentrations in the CSF or via the amyloid-specific radiotracer 18F-flutemetamol with PET. The SuStaIn analysis revealed three distinct subtypes, each characterized by unique patterns of spatiotemporal evolution of brain atrophy: neocortical, limbic and brainstem. In the neocortical subtype, a reduction in brain volume occurred in the frontal and parietal cortices in the earliest disease stage and progressed across the entire neocortex during the early stage, although with relative sparing of the striatum, pallidum, accumbens area and brainstem. The limbic subtype represented comparative regional vulnerability, which was characterized by early volume loss in the amygdala, accumbens area, striatum and temporal cortex, subsequently spreading to the parietal and frontal cortices across disease stage. The brainstem subtype showed gradual rostral progression from the brainstem extending to the amygdala and hippocampus, followed by the temporal and other cortices. Longitudinal MRI data confirmed that 77.8% of participants at the 2-year follow-up and 84.0% at the 4-year follow-up were assigned to subtypes consistent with estimates from the cross-sectional data. This three-subtype model aligned with empirically proposed subtypes based on age at onset, because the neocortical subtype demonstrated characteristics similar to those found in the old-onset phenotype, including older onset and cognitive decline symptoms (P < 0.05). Moreover, the subtypes correspond to the three categories of the neuropathological consensus criteria for symptomatic patients with Lewy pathology, proposing neocortex-, limbic- and brainstem-predominant patterns as different subgroups of α-synuclein distributions. Among the subtypes, the prevalence of biomarker evidence of amyloid-β pathology was comparable. Upon validation, the subtype model might be applied to individual cases, potentially serving as a biomarker to track disease progression and predict temporal evolution.

Clinical outcome of ultrasonographic detected undifferentiated synovitis in patients with arthralgia

BackgroundIn the early stages of rheumatic diseases, individuals may present with nonspecific musculoskeletal symptoms (such as arthralgia) in the absence of clinical synovitis. Ultrasound (US) looks potentially helpful, particularly in the absence of symptomatic arthritis. This research aims to study the clinical outcomes of undifferentiated synovitis detected by ultrasound in patients who complain of arthralgia and their predicting factors.ResultsFrom 174 patients with arthralgia, 42% of cases went into remission, and 58% remained as persistent inflammatory arthritis (PIA) (26.4% persisted as undifferentiated arthritis, 31.6% differentiated into specific rheumatic diseases of whom 9.2% became rheumatoid arthritis, 6.3% developed spondyloarthropathy, and other diseases) after 2 years of follow-up. Regression analysis showed that patients with Power Doppler (PD) grade (I or II), grayscale (GS) synovitis grade (II or III), and GS synovitis ≥ grade II in one wrist were significant predictors for PIA in undifferentiated arthralgia’s patients.ConclusionsApproximately 60% of patients with arthralgia developed inflammatory arthritis (IA) after 2 years of follow-up, with 77% of them having US synovitis at the onset of the study. A positive PD signal, grade (II or III) GS synovitis, or ≥ grade II at one wrist were all independently related to the development of PIA in arthralgia patients.

Chemogenetic neuronal silencing decouples c-Jun activation from cell death in the temporal cortex.

Initial symptoms of neurodegenerative diseases are often defined by the loss of the most vulnerable neural populations specific to each disorder. In the early stages of Alzheimer's disease, vulnerable circuits in the temporal lobe exhibit diminished activity prior to overt degeneration. It remains unclear whether these functional changes contribute to regional vulnerability or are simply a consequence of pathology. We previously found that entorhinal neurons in the temporal cortex undergo cell death following transient suppression of electrical activity, suggesting a causal role for activity disruption in neurodegeneration. Here we demonstrate that electrical arrest of this circuit stimulates the injury-response transcription factor c-Jun. Entorhinal silencing induces transcriptional changes consistent with c-Jun activation that share characteristics of gene signatures in other neuronal populations vulnerable to Alzheimer's disease. Despite its established role in the neuronal injury response, inhibiting c-Jun failed to ameliorate entorhinal degeneration following activity disruption. Finally, we present preliminary evidence of integrated stress response activity that may serve as an alternative hypothesis to what drives entorhinal degeneration after silencing. Our data demonstrate that c-Jun is activated in response to neuronal silencing in the entorhinal cortex but is decoupled from subsequent neurodegeneration.

Evaluation of Circulating Tumor DNA and Carcinoembryonic Antigen Levels and Relationship with Clinicopathological Risk Factors and Prognostic Indices in Colorectal Cancer Patients

Objective: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. ctDNA has emerged as a promising biomarker for CRC management, offering real-time insights into tumor burden and genetic mutations. This study investigates the correlation between CEA levels, ctDNA, clinicopathological factors, and treatment outcomes in early and advanced CRC patients. Methods: The study retrospectively analyzed data from CRC patients, including early-stage disease and metastatic disease. ctDNA levels, demographic data, and clinical parameters such as CEA, inflammatory indexes, and tumor characteristics were evaluated to determine correlations with treatment outcomes. Results: The study included 20 patients, with 60% diagnosed at the metastatic stage. The study found no statistically significant correlation between ctDNA levels and disease stage, recurrence, or overall survival. While CEA and ctDNA levels were measured, they did not demonstrate a significant relationship with treatment outcomes. Notably, ctDNA levels were higher in metastatic patients, though this was not statistically significant. Conclusion: Despite its potential, the integration of ctDNA as a routine biomarker in CRC care faces challenges, including variability in measurement techniques and cost-effectiveness. However, ctDNA's ability to guide personalized treatment strategies and monitor disease recurrence holds promise. The study's findings align with previous research, suggesting ctDNA as a poor prognostic indicator, though further research is needed. ctDNA represents a significant advance in CRC management, offering non-invasive, real-time insights into tumor dynamics. Ongoing research is expected to solidify its role in personalized treatment planning, potentially leading to more effective and tailored therapies for CRC patients.

Minimally Invasive Transhiatal Esophagectomy Using Antegrade Inversion Technique in Esophageal Cancer: 10-Year Experience from a Tertiary Care Center.

Background: Esophageal cancer surgery aims for curative intent but carries high complication rates. Transthoracic esophagectomy is the dominant approach, however, transhiatal esophagectomy (THE) offers selective advantages in certain clinical scenarios. Minimally invasive THE (MI-THE) is an evolving technique with limited data. Methods: This retrospective study reviewed 38 patients with esophageal cancer who underwent MI-THE using "Antegrade Inversion Technique" between 2013 and 2023 at a tertiary care center. Perioperative outcomes were analyzed. Data were presented as mean with standard deviation, median with interquartile range, and percentages. Results: Most patients (86.8%) had early-stage cancer. Median operative time was 375 minutes, hospital stay was 8 days, and intensive care unit stay was 3 days. All patients achieved a negative resection margin. Pleural effusion (57.9%) was the most common complication, followed by pneumothorax (31.6%) and surgical site infection (15.8%). Anastomotic leak rate was 13.2%. There was no mortality. Conclusions: MI-THE appears safe and feasible with encouraging perioperative outcomes, particularly for early-stage disease and high-risk patients. While potentially offering advantages over open THE, further research is needed to definitively establish its role compared to traditional approaches.

Elevated Netrin-4 Expression and Its Action in Infrapatellar Fat Pad.

Knee osteoarthritis (KOA) is a degenerative joint disease characterized by inflammation and cartilage degradation. The infrapatellar fat pad (IFP), located beneath the patella within the knee joint, serves as a key anatomical structure involved in cushioning and supporting the knee. It is also an active endocrine organ that secretes various bioactive substances, potentially influencing the local inflammatory environment and contributing to KOA pathogenesis. Netrin-4 (NTN4), a protein primarily known for its role in neuronal guidance, has been implicated in various non-neuronal functions, including inflammatory processes and tissue remodeling. This study aims to explore the involvement of NTN4 in KOA, focusing on its expression in the IFP and its potential impact on disease progression. This study involved 82 patients with radiographically confirmed KOA undergoing total knee arthroplasty (TKA). The correlation between NTN4 expression and OA pathology, including Kellgren-Lawrence (K/L) grades, was investigated. NTN4-expressing cells were identified in the stromal vascular fraction, including fibroblastic, hematopoietic, and endothelial cells of the IFP. To elucidate the molecular effects of NTN4, RNA sequencing (RNA-seq) was performed on fibroblastic cells treated with recombinant NTN4. Subsequent quantitative PCR (qPCR) was used to validate the RNA-seq findings. NTN4 expression was significantly elevated in the IFP of patients with advanced KOA (K/L grades 3 and 4) compared to those with early-stage disease (K/L grade 2). Higher NTN4 expression was found in fibroblastic cells, and RNA-seq analysis revealed upregulation of genes associated with pro-inflammatory pathways, including IL-17 and TNF-α signaling, and matrix degradation. Notably, genes including IL6, MMP1, CXCL1, and CXCL8 were significantly elevated, as confirmed by qPCR, indicating NTN4's role in promoting an inflammatory and catabolic environment. Our findings suggest that NTN4 plays a significant role in the pathogenesis of KOA by promoting inflammation and matrix degradation within the IFP. Although NTN4 expression was not directly correlated with clinical symptoms, its elevated expression in fibroblastic cells and influence on inflammatory and degradative pathways suggest a potential mechanism for exacerbating joint damage. Targeting NTN4 could offer a novel therapeutic approach to mitigating inflammation and slowing disease progression in KOA, ultimately improving patient outcomes. Further research is needed to clarify NTN4's specific roles and therapeutic potential in OA management.

Data set for the reporting of lung cancer: recommendations from the International Collaboration on Cancer Reporting (ICCR).

Lung cancer is the leading cause of cancer related deaths worldwide, although some patients with early-stage disease can be cured with surgical resection. Standardised reporting of all clinically relevant pathological parameters is essential for best patient care and is also important for ongoing data collection and refinement of important pathological features that impact patient prognosis, staging and clinical care. Using the established International Collaboration on Cancer Reporting (ICCR) procedure, a representative international expert panel of nine lung pathologists as well as an oncologist was convened. Essential core elements and suggested non-core elements were identified for inclusion in the resected lung cancer pathology data set based on predetermined levels of evidence as well as consensus expert opinion. A lung cancer histopathology reporting guide was developed that includes relevant clinical, macroscopic, microscopic and ancillary testing. Critical review and discussion of current evidence was incorporated into the new data set including changes from the 2021 World Health Organisation (WHO) Classification of Thoracic Tumours, fifth edition, new requirements for grading invasive non-mucinous adenocarcinomas, assessment of response to neoadjuvant therapy and requirements for molecular testing in early-stage resected lung carcinomas. This ICCR data set represents incorporation of all relevant parameters for histology reporting of lung cancer resection specimens. Routine use of this data set is recommended for all pathology reporting of resected lung cancer and it is freely available worldwide on the ICCR website (https://www.iccr-cancer.org/datasets/published-datasets/). Widespread implementation will help to ensure consistent and comprehensive pathology reporting and data collection essential for lung cancer patient care, clinical trials and other research.